Idiopathic pulmonary fibrosis (IPF) is a devastating lung disease. Patients face a 50% three-year mortality rate and no proven effective therapy exists. The primary goal of this project is to establish a medicinal chemistry core facility that supports translational research projects in our shared objective to develop new drug therapies for IPF. Project Pis hypothesize that IPF is a consequence of on-going epithelial stress and apoptosis, which leads to activation of extracellular latent TGF-beta by the alpha-v beta-6 integrin on alveolar epithelial cells, which in turn induces progressive fibrosis at least in part through induction of epithelial to mesenchymal transformation. A concept that unifies our drug development approach is that each of the mechanisms can be optimally targeted by delivering drug agents directly to the alveolar epithelial cells via the airways. Delivery by inhalation has the potential to minimize unwanted systemic effects, especially when the drug agent has low systemic availability. Early screening hits, tool compounds and lead compounds that target each of these mechanisms have been identified by Project Pis. The medicinal chemistry core will work collaboratively to optimize these compounds for superior potency, selectivity and pharmacokinetic profile (rapid clearance upon systemic absorption) to increase efficacy and therapeutic index in animal models of IPF with inhaled delivery. The objective for all of these activities is to identify clinical candidates for advancement to clinical trials in IPF under the planned second phase of this tPPG.